Influenza virus causes an estimated 1 million severe infections in children each year. In spite of intensive research, many questions remain about the development of immunity and correlates of protection from influenza infection in children. To undertake a detailed investigation of the development of immunity to influenza virus infection in children, we have been conducting a large pediatric cohort study of influenza in children in Nicaragua for over 8-years. In addition to banked longitudinal serum samples, we have detailed information on clinical laboratory-confirmed influenza virus infections and demographic and nutritional status on all children. Our pediatric cohort study presents a rare and invaluable opportunity to study the developmental stages of the cross-reactive immune response in children. Our central hypothesis is that cross-reactive HA antibody response, like homologous HA antibody response, is a key protective immune mechanism against influenza infection and that cross-reactive antibody response is acquired as a part of the immune maturation process in children. We will take advantage of the innovative use of epidemiologic data and biologic samples of unprecedented completeness and quality, and state-of-the-art Bayesian statistical modeling to investigate the development of the immune response to influenza infection in children. In Aim 1, we will characterize the developmental stages of the acquisition of strength, cross-reactivity and persistence of hemagglutinin antibody response by years of age and gender. In Aim 2, we will investigate whether developmental acquisition of strength, cross-reactivity and persistence of hemagglutinin antibody response depends on early life influenza exposure. In Aim 3, we will evaluate the relationship between hemagglutinin antibody response and persistence, and risk of recurrent influenza infections and severity in children. This proposal addresses major gaps in knowledge on cross protective antibodies in children and their effect on influenza infection risk and disease severity. Currently, vaccination is the best method to reduce the heavy burden of influenza in children. However, the efficacy of current vaccines is clearly lower in children and vaccine effectiveness is strongly affected by antigenic drift. A bettr understanding of cross protective antibodies in children will inform strategic use and design of broadly-protective influenza vaccines and will further expand the benefits that vaccination has been providing. This is particularly important since children are at high risk of infection and ther immune system is still undergoing development. In addition it is critical that we further our understanding of children's risk of infection and transmission with respect to their immune development. Our proposed study is thus timely and well-poised to have substantial public health and scientific impact.